Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish.
Am J Hum Genet
; 90(4): 661-74, 2012 Apr 06.
Article
em En
| MEDLINE
| ID: mdl-22482805
ABSTRACT
Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFß superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteogênese
/
Proteína Morfogenética Óssea 1
Limite:
Animals
/
Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Singapura